This study examines the neuron's response to the simultaneous presence or sequential appearance of multiple neuromodulators. My approach is to investigate the determinants of adenylate cyclase activity at the level of the plasma membrane of cultured neuroblastoma cells. This multicomponent enzyme synthesizes cyclic AMP, a second messenger that regulates intracellular functions. Cell surface receptors for prostaglandins are stimulatory regulators of adenylate cyclase; receptors for muscarinic agonists or opiates are inhibitory regulators. The goal of these studies is to determine the mechanisms of receptor mediated inhibition and the ensuing adaptive response of the cells to chronic stimulation by inhibitory agonists. It is hoped that these experiments will advance our understanding of how neurons in the brain "learn" to respond to normal synaptic inputs and develop tolerance drugs.